Obesity is prevalent in one third of American adults and children and costs the American health care system billions of dollars yearly. The major impact of obesity on patients is the development of obesity-related comorbidities, such as type 2 diabetes mellitus (T2DM). Given the extensive cost to society, as well as the impact of these conditions on patients, establishing the link between obesity and T2DM is paramount to effectively treating and decreasing the prevalence of T2DM. One of the possible mechanisms linking obesity and T2DM is through inflammatory pathways. Accumulating evidence indicates that the CNS is responsive to hormones and nutrients regulating glucose homeostasis and that dysregulation of this system may occur with NF?B activation. However, the potential CNS regulation of this pathway on peripheral metabolic processes has not been studied. In this proposal, Dr. Sisley will focus on the effect of one specific brain inflammatory pathway, NF?B, on glucose homeostasis. Her preliminary data have revealed the ability of a single dose of an NF?B inhibitor to improve glucose tolerance. The specific aims of her proposal will examine the mechanistic link between CNS inhibition of the NF?B pathway on glucose homeostasis using acute inhibition studies. She will also investigate the effect of CNS NF?B inhibition on inflammatory markers in peripheral tissues. The primary goal of this mentored fellowship award is to advance Dr. Sisley forward in her pursuit of an independent research career. PUBLIC HEALTH RELEVANCE: The proposed studies are expected to elucidate the role of CNS NF?B in the regulation of glucose homeostasis and peripheral inflammation. This contribution is significant because it will provide new information on the linkage between obesity and T2DM and may identify new potential therapeutic options to alleviate the societal burden of T2DM.